The long-term goals of my research are to understand the cellular and molecular mechanisms that control regeneration of descending axons from brain neurons and recovery of locomotor function following spinal cord injury. The lamprey, a "lower" vertebrate, has many experimental advantages for examining the factors that control functional regeneration. Between 2-8 weeks following transection of the rostral spinal cord in larval lamprey, locomotor movements gradually return to normal, and muscle activity can be recorded at progressively greater distances below the lesion. With increasing recovery times, descending axons from brainstem neurons, including reticulospinal (RS) neurons that are thought to initiate locomotor activity, regenerate to progressively more caudal levels of the spinal cord, However, complete restoration of descending projections is not required for recovery of function. Substantial recovery of locomotor function can occur at a particular level of the body below a spinal cord lesion when the descending projections to the corresponding level of the spinal cord are reduced or absent. These results suggest that in higher vertebrates, recovery of locomotor function might occur without substantial regeneration, provided that additional compensatory mechanisms are available. The present study will use neurophysiological, behavioral, and anatomical techniques to examine four aspects of functional regeneration and restoration of locomotor initiation in spinal cord-transected lamprey. (I) The biophysical and morphological properties of axotomized descending brain neurons, particularly RS neurons, will be examine& to determine if the time course of changes in these properties is related to regeneration of descending brainstem projections, synaptic reconnection, and behavioral recovery. (II) Paired intracellular recordings will be made between regenerated RS neurons and neurons in spinal locomotor networks to determine if synaptic specificity is necessary for behavioral recovery. (III) Synaptic inputs and activity patterns in RS neurons will be determined before, during, and after behavioral recovery to investigate plasticity in these neurons relative to the time course of regeneration and synaptic reconnection with spinal targets. (IV) At short recovery times, descending axons from brainstem command neurons have regenerated for short distances below the lesion, and descending propriospinal neurons appear to relay descending drive to locomotor networks in the more caudal areas of the spinal cord. Physiological and anatomical experiments will be used to examine these important descending propriospinal neurons. Together, these experiments will provide critical information that will elucidate the mechanisms controlling spinal cord regeneration and behavioral recovery following spinal injury.